According to the World Health Organization (WHO) report (2000), 100 million newborns and children received BCG in 1992 through WHO/UNICEF program. Even though majority of the global population is vaccinated with BCG, tuberculosis continues to kill some 3 million people a year. Further, about one-third of the world population remains latently infected with M. tuberculosis. Hence, the only available vaccine BCG is both unpredictable and highly variable. Doubtful efficacy of BCG vaccination has put the scientific community to challenge to urgently develop effective means of vaccination against M. tuberculosis. 
Unfortunately, the global problem of tuberculosis is compounded by the additional problems of AIDS and emergence of Multi Drug Resistant (MDR) strains of M. tuberculosis. Moreover, a new question has arisen regarding the safety of BCG in HIV-infected individuals. A small number of cases of disseminated BCG-osis have been reported among children who received BCG vaccine and were subsequently found to be HIV seropositive (Von Reyn, et. al. Lancet 1987:ii:669-672; Braun, et. al., Pedietr. Infect. Dis. J. 1992:11:220-227; Weltman, et. al., AIDS 7:1993:149). WHO currently recommends discontinuing the use of BCG vaccine in children showing overt signs of immunodeficiency (World Health Organization. Tuberculosis fact sheet number 104, August 2002).
BCG has been extensively utilized globally and in spite of its intrepid use, tuberculosis has still become the fastest spreading disease not only in developing countries but also in the industrialized world. Its doubtful efficacy in controlled trials has increased the concern about its use as a vaccine (Bloom, B. R. et. al., Annu. Rev. Immunol. 10:1992:453). Furthermore, the extensive clinical trials done in Chenglepet, India showed similar extent of protection in BCG-vaccinated and unvaccinated individuals, indicating that it induced zero protection (Narayanan Indian J Med Res. 2006, 123 (2): 119-124). Thus it is obvious that BCG vaccination does not prevent transmission.
Another insight for BCG failure is provided by the intracellular location of the mycobacterium. Electron microscopic findings indicate that BCG remains essentially within the phagolysosomes after in vitro infection of macrophages, whereas virulent M. tuberculosis (strain H37Rv) can escape from the phagolysosome and enter the cytoplasm (McDonough, et. al., Infect. Immun. 61:1993:2763). This may be relevant insofar as it is the antigens in the endosomal compartment of antigen-presenting cells that are presented in conjunction with MHC class II determinants to CD4+ T helper cells, whereas cytoplasmic antigens are presented in association with the Major Histocompatibility Complex (MHC) class I determinants to CD8+ Cytotoxic T cells (CTL). This explains why M. tuberculosis is more dependent for its elimination on MHC class I-restricted CTL than BCG and suggests that BCG may not be very effective in eliciting MHC class I-restricted CTL (Stover, et. al., Nature 351:1991:456). In this context, Rich, 1951, Kaufman et al 2008, commented that recovery from infection with M. tuberculosis provided stronger protection against future tuberculosis than could BCG. Hence, the effective resistance to M. tuberculosis infection will require participation both of specific CD8+ CTL to lyse macrophages or parenchymal cells unable to restrict their infection and of specific CD4+ T cells able to produce IL-2, IFN-γ, TNF-α, and other lymphokines involved in macrophage activation.
Recent series of studies have suggested that M. tuberculosis/environmental mycobacteria actively inhibit bacterial antigen processing and presentation by MHC-I and MHC-II pathways, thus slowing the emergence of protective adaptive immunity (Wolf A J, Linas B, Trevejo-Nuñez G J, Kincaid E, Tamura T, Takatsu K, Ernst J D. Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. J Immunol. 2007, 179(4):2509-19). Furthermore, M. tuberculosis also impairs in vivo antigen processing of dendritic cells (Wolf A J, Linas B, Trevejo-Nuñez G J, Kincaid E, Tamura T, Takatsu K, Ernst J D. Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. J Immunol. 2007, 179(4):2509-19). Hence failure of BCG in endemic areas like India can be suggested to be due to the extensive mycobacterial load in the environment. Consequently, antigen processing pathways might be seriously compromised. To overcome these problems, a suitable approach in TB-endemic areas may be to devise a vaccine that bye pass antigen processing. Hence peptides can be suitable alternative since they do not require extensive antigen processing.
Peptides can be potentially used as vaccines. They bypass antigen processing because they can directly bind to MHC class I and II molecules; hence can be presented to both CD4 and CD8 T cells. Therefore the environmental mycobacterial load will not affect their efficacy. Unfortunately, conventional peptide vaccines have been plagued by two problems. Firstly, peptides are poorly immunogenic. They have to be administered with powerful adjuvants to elicit an immune response. The number of adjuvants available for humans are not only extremely limited but are also very expensive. Therefore such a strategy is economically not viable for mass vaccination, especially in developing countries, where tuberculosis incidence is maximal. Secondly, most of the antigenic peptides derived from mycobacterial antigen's binding is restricted to just one or two Human Leukocyte Antigen (HLA) alleles. HLA is the most polymorphic gene system in the entire human genome. Therefore it is difficult for the peptides to elicit an immune response in a genetically diverse human population, which is thoroughly polymorphic. These reasons have mired progress in peptide vaccinology. But if these problems are circumvented, peptide vaccine can be extremely effective than any other potential candidates; particularly in a situation where antigen processing is stalled by environmental agents. Further, promiscuous peptides, which can bind to many HLA alleles, can solve the problem of HLA restriction. Therefore identification of promiscuous peptides from antigens of M. tuberculosis, especially secretory antigens, would be of great importance in developing a vaccine. Promiscuous T cell epitopes are peptides that bind to more than one HLA allele and hence may elicit a T cell response overcoming MHC restrictions. They can be identified by conventional biochemical in vitro HLA binding assays, immunologic assays such as T cell proliferation, and activation or effector response such as secretion of cytokines (Agrewala J N, Deacock S, Jurcevic S, Wilkinson R. Peptide recognition by T-cell clones of an HLA-DRB1*1501/*0901 heterozygous donor is promiscuous only between parental alleles. Peptide recognition by T-cell clones of an HLA-DRB1*1501/*0901 heterozygous donor is promiscuous only between parental alleles. Hum Immunol. 1997 June; 55(1):34-8; Agrewala J N, Wilkinson R J. Differential regulation of Th1 and Th2 cells by p91-110 and p21-40 peptides of the 16-kD alpha-crystallin antigen of Mycobacterium tuberculosis. Differential regulation of Th1 and Th2 cells by p91-110 and p21-40 peptides of the 16-kD alpha-crystallin antigen of Mycobacterium tuberculosis. Clin Exp Immunol. 1998 December; 114(3):392-7; Agrewala J N, Wilkinson R J. Influence of HLA-DR on the phenotype of CD4+T lymphocytes specific for an epitope of the 16-kDa alpha-crystallin antigen of Mycobacterium tuberculosis. Influence of HLA-DR on the phenotype of CD4+T lymphocytes specific for an epitope of the 16-kDa alpha-crystallin antigen of Mycobacterium tuberculosis. Eur J Immunol. 1999 June; 29(6):1753-61). They may also be selected based on bioinformatic analysis using T cell epitope prediction programs.
The pre-requisite for the effective priming of the adaptive immune system is the maturation of APCs, whose function is to engulf the pathogens, process and present it to T cells. Antigen presenting cells possess Pattern Recognition Receptors (PRRs) which recognize the conserved motifs known as Pathogen Associated Molecular Patterns (PAMPs) of the pathogens. Triggering of PRRs by PAMPs acts as a “danger signal” (Medzhitov R, Janeway C A Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell. 1997 Oct. 31; 91(3):295-8), which results in maturation of APCs and culminates in mounting an adaptive immune response against that pathogen. Toll-Like Receptors are one such critical PRRs which link the innate and adaptive arms of immunity. Adjuvants functions by binding to TLRs and thereby delivering signals necessary for the activation of APCs. Recently, it has been demonstrated very elegantly that there is robust increase in the immune response if TLR triggering moiety and the antigen are physically associated (Blander J M, Medzhitov R Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature. 2006, 440(7085):808-12).
Expression of costimulatory molecules, enhanced antigen presentation and production of cytokines and chemokines is also upregulated when APCs are engaged with TLRs. In essence, TLRs are a family of transmembrane receptors by which APCs recognize the conserved PAMPs that distinguish the infectious agents from self. Over the past few years, the macromolecules recognized by TLRs have been identified. Agonists for TLRs include the inflammatory mediators tri-acyl lipopeptides (TLR1), lipoteichoic acid (TLR2), dsRNA (TLR3), lipopolysaccharide (TLR4), flagellin (TLR5), diacyl lipopeptides (TLR6), imidazoquinolines (TLR7, TLR8) and CpG oligonucleotides (TLR9) (Akira S, Sato S. Toll-like receptors and their signaling mechanisms. Scand J Infect Dis. 2003; 35(9):555-62). Toll like receptors constitute an essential part of the innate immune system but they have also been equally important in adaptive immune system. Antigen presentation without this danger signal leads to anergy or tolerance.
Hence, an analysis of the hitherto reported literature reveals that free peptides may not elicit an optimum immune response. Since TLR triggering is essential for activation of the APCs, physically coupling (covalent or encapsulated form) promiscuous peptides/epitopes to TLR ligands to trigger effective immune response may be an exceptional proposition. Most of the TLR ligands are lipid moieties but TLR 3, 7 and 9 are triggered by nucleic acids. Triggering of TLRs especially, TLRs 2, 4 and 9 results in Th1 responses. Hence, it is specially proposed that these peptide-TLR ligands for 2 or 4 or 9 would be very effective in protecting against M. tuberculosis. 
Despite several potential advantages none of the totally synthetic peptide epitope-based vaccines are yet licensed/available for human or animal use. The poor immunogenicity of peptides in the absence of co-administered adjuvants and the paucity of adjuvant systems suitable for human use has limited the development of viable epitope-based vaccines.
Accordingly, it may be summarized that non-living vaccines fails to impart protection against tuberculosis due to the use of inadequate adjuvants. The currently-used adjuvants for human vaccines (based on aluminum salts) are only effective in vaccines that require a humoral response since they bias the immune response towards the Th2 pole, which can only help in protecting against extra-cellular infections. The available adjuvants have limited use due to their very high cost. Thus, an effective way to overcome this predicament is to incorporate lipid groups into the promiscuous-peptides/subunit vaccines which will then have self-adjuvanting properties.